Crit Care Clin 22 (2006) 221 – 243

Effect of Vasoactive Therapy on

Cerebral Circulation
Denise H. Rhoney, PharmDT, Xi Liu-DeRyke, PharmD
Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences,
Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA

The incidence of new and recurrent stroke is approximately 700,000 annually

in the United States, resulting in 162,672 deaths and $56.8 billion in health care
expenditures, which makes stroke a principal cause of disability and an economic
burden on society [1]. Acute ischemic stroke (AIS) accounts for more than 80%
of all stroke, and hemorrhagic stroke, including intracerebral hemorrhage (ICH)
and subarachnoid hemorrhage, makes up the remaining 20%. Malignant hyper-
tension is a significant risk factor and major complication of all acute strokes.
Approximately two thirds of the patients who have a first stroke have a history
of hypertension [1]. In addition, acute hypertension is observed in 80% of pa-
tients after a stroke, irrespective of a previous history of hypertension. This initial
increase in the blood pressure is believed to be a protective mechanism by the
brain for maintaining cerebral perfusion pressure (CPP). A persistent increase in
blood pressure can lead to hemorrhagic transformation, rebleeding, or brain edema,
however, which may result in secondary stroke or further neurologic damage.
Managing blood pressure during the acute phase of a stroke is a challenge. In
the International Stroke Trial (IST), high and low blood pressures were inde-
pendent prognostic factors for poor outcomes [2]. This indicates that a delicate
balance of blood pressure management is vital in ensuring a successful outcome
in patients with brain injury. Additionally, a spontaneous decrease in blood pres-
sure without receiving treatment was documented a few days after stroke onset
[3,4]. This observation further complicates the decision of whether to treat
hypertension acutely in patients with stroke. There is a lack of consensus on

D.H. Rhoney has received an unrestricted educational grant from ESP Pharma.
T Corresponding author.
E-mail address: drhoney@wayne.edu (D.H. Rhoney).

0749-0704/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2006.02.009 criticalcare.theclinics.com
222 rhoney & liu-deryke

whether to treat the transient elevation in blood pressure after stroke and on
how aggressive blood pressure should be lowered in AIS and primary ICH. The
general belief is that acute hypertension should be treated so as to avoid sec-
ondary neuronal damage; however, adequate perfusion to the brain must also
be maintained. The management of acute hypertension after stroke varies greatly
throughout the world among neurologists and neurosurgeons despite existing
guidelines. Therefore, understanding cerebral physiology and the pharmaco-
kinetic and pharmacodynamic properties of antihypertensive agents is vital in
guiding therapeutic decisions in these patients.

Cerebrovascular physiology

The pathophysiology of stroke is a multifaceted process involving cellular and

metabolic abnormalities (ion imbalance, inflammation, and cell death), endothe-
lial damage, and vascular changes. The focus of this review is on understanding
the vascular changes that occur after stroke and how this aids in decision making.

Normal physiology

When considering patients with acute neurologic disease, maintenance of

cerebral blood flow (CBF) is the key goal. In healthy individuals, the brain has
little capacity to store oxygen; therefore, it is imperative to maintain a relatively
constant CBF to ensure adequate cerebral oxygen supply for the metabolic re-
quirement. To understand the relation among mean arterial pressure (MAP),
intracranial pressure (ICP), CBF, and CPP, it is important to have a thorough
knowledge of the normal cerebral physiology. CBF is regulated through CPP and
cerebral vascular resistance (CVR), and these relations are expressed mathemati-
cally as follows:

CPP ¼ MAP  ICP

CBF ¼ CPP=CVR

The body protects the brain by a hemostatic mechanism known as cerebral

autoregulation. Autoregulation can be defined as the inherent ability of arteries to
vasodilate (decrease in CVR) or vasoconstrict (increase in CVR) in response to
changing perfusion pressure to maintain a relatively stable CBF (Fig. 1). CPP
generally approximates MAP when the brain is free of trauma or injury. Under
normal circumstances, the brain is able to maintain a constant CBF of approxi-
mately 50 mL per 100 g/min over a wide range of MAP ranging from approxi-
mately 60 to 150 mm Hg. The brain resides within a rigid cranial vault that
is protected by the skull. Within this incompressible compartment, brain tissue
(80%), cerebral spinal fluid (10%), and blood (10%) are in a state of equilibrium.
 cerebral circulation vasoactive therapy 223

Fig. 1. Normal cerebral autoregulation curve. With normal cerebral physiology, the brain maintains
constant CBF under a wide range of MAPs (range: 60–150 mm Hg). When MAP falls below or
exceeds the limits of autoregulation, CBF becomes pressure dependent. (From Lang EW. Cerebral
vasomotor reactivity testing in head injury: the link between pressure and flow. J Neurol Neurosurg
Psychiatry 2003;74(8):1054; with permission.)

Any change in one component of the brain needs to be compensated for by a

decrease in one or more of the other components. When the intracranial vault
volume is disturbed, ICP increases, which causes a reduction in CPP. The reduc-
tion in CPP can decrease CBF when autoregulation is disrupted (see Fig. 1).
After a decrease in CBF, the body initially compensates by increasing the
oxygen extraction fraction from the blood. Cerebral ischemia eventually occurs
when the pressure remains low or below the lower limit of autoregulation,
however. Conversely, cerebral vessels constrict as MAP rises and the vascular
endothelial cells become stretched. Eventually, the cerebral vessels can no longer
constrict effectively against the high perfusion pressure, and autoregulation fails,
leading to cerebral edema or hemorrhage. In patients with chronic hypertension,
the autoregulatory curve is shifted to the right toward higher pressures. There-
fore, lowering the blood pressure to a ‘‘normal range’’ in patients with poorly
controlled chronic hypertension may accelerate end-organ damage because of the
lack of oxygen perfusion to the tissues. In addition, patients with neurologic
injury (eg, stroke) may have impaired autoregulation, and CBF becomes pressure
dependent [5]. In this scenario, a small change in blood pressure can have a
drastic impact on CBF, and thus can affect oxygen supply to the brain.
Overall, the debate for managing blood pressure during the acute phase of
stroke centers on two theories. First, hypertension is a risk factor for developing
stroke, and elevated blood pressure during the acute phase can lead to neurologic
224 rhoney & liu-deryke

deterioration by promoting cerebral edema and hemorrhage. Second, actively

lowering blood pressure during the acute phase may adversely affect cerebral
perfusion, resulting in further stroke and worsening neurologic outcome. It is
essential to understand the evidence supporting or negating these theories in AIS
and ICH to assess when it is appropriate to initiate acute antihypertensive therapy.

Significance of hypertension in acute ischemic stroke

Before considering acute blood pressure management in AIS, understanding

the concept of the penumbra is crucial (Fig. 2). Ischemic stroke results from
occlusion of cerebral vessels, which leads to a decrease in blood flow and dep-
rivation of oxygen supply to the brain. The normal CBF is approximately 50 mL
per 100 g/min. In the focal region with infarction, CBF is generally diminished
(less than 10 mL per 100 g/min). This hypoperfusion results in permanent neu-
ronal damage, and this part of the tissue is known as the ischemic core. The
ischemic penumbra is the area immediately surrounding the ischemic core, where
CBF is decreased (10–20 mL per 100 g/min), but the tissue can be salvageable if
reperfusion is established. This concept was first proposed by Astrup and col-
leagues [6] in 1981 and has since been validated with imaging studies using
positron emission tomography, diffusion-weighted imaging, and MRI. Within the
penumbra, blood flow is sufficient to maintain cellular viability acutely but not
sufficient for normal cellular function. It is therefore essential to provide adequate
perfusion to this area promptly so as to limit the extension of the ischemic core.

Normal Flow

Penumbra

Ischemic
core

Fig. 2. Relation between ischemic core, penumbra, and normal cells after ischemic stroke. After AIS,
CBF diminishes (b10 mL per 100 g/min) within a focal region and immediate cell death occurs,
resulting in an ischemic core. The surrounding tissue, called the penumbra, is supplied by decreased
CBF (10–20 mL per 100 g/min); however, cell death can be avoided if reperfusion to the area is
established. Within unaffected cerebral tissues, CBF is approximately 50 mL per 100 g/min.
 cerebral circulation vasoactive therapy 225

The goal of keeping adequate perfusion and oxygenation to the brain lays the
foundation for the argument not to lower blood pressure acutely after stroke.
Eames and coworkers [7] found a loss of integrity of autoregulation in pa-
tients with AIS after they were matched with individuals without stroke for age,
gender, and MAP. The results confirmed the theory that neurologic injury leads to
impairment of cerebral autoregulation, and CBF becomes pressure dependent.
Aggressive lowering of the blood pressure thus results in a reduction in CBF and
compromises the perfusion and oxygenation to the brain. Okumura and col-
leagues [8] sought to delineate the correlation between admission blood pressure
and mortality and how the relations may differ in stroke types in a large popu-
lation. A total of 2101 patients, 1004 with AIS and 1097 with primary ICH, were
enrolled and eligible for the analysis. In patients with ischemic stroke, systolic
blood pressure (SBP; b130 or N210 mm Hg) and diastolic blood pressure (DBP;
b 70 or N110 mm Hg) were associated with a 1.6- to 3.5-fold risk of mortality
in 30 days after stroke. This finding confirmed the U-shaped relation of blood
pressure and outcomes in patients with ischemic stroke. In addition, the study
demonstrated that patients with a history of hypertension needed a higher blood
pressure to survive compared with those without such a history. This finding
supported the theory of the autoregulation curve shifted toward the right in pa-
tients with chronic uncontrolled hypertension, in which case, overaggressive
lowering of blood pressure may adversely affect the cerebral perfusion. In fact,
this evidence may suggest the need to elevate blood pressure with vasopressor
agents in an effort to increase CPP and improve CBF. Induced hypertension has
not become a common practice outside the setting of severe hypotension and
would require further clinical study, although there are recent reports evaluating
this treatment modality [9,10].
Meanwhile, a meta-analysis [11] examined the relation between the admis-
sion blood pressure and clinical outcomes in more than 10,000 patients, in-
cluding patients with AIS and ICH. Elevated SBP (150–200 mm Hg), MAP
(140–145 mm Hg), and DBP (90–115 mm Hg) were associated with early recur-
rence, increased disability, and death, irrespective of stroke type. In addition, sev-
eral observational studies have shown that elevated blood pressure after ischemic
infarct leads to brain edema and hemorrhagic transformation, suggesting that
there may be a scientific base for acutely lowering blood pressure after stroke.
Because of the conflicting facts and limited evidence, blood pressure manage-
ment in AIS remains controversial. Acknowledging limitations in the currently
published literature, the Stroke Council of the American Stroke Association made
the following recommendation regarding blood pressure management in patients
with AIS [12,13]. In patients who are not eligible for thrombolytic therapy, blood
pressure is treated only when the SBP is greater than 220 mm Hg or the DBP is
greater than 140 mmHg, and the goal is to lower the blood pressure by 10% to
15% from baseline. The threshold of treatment is lower in patients who are
eligible for thrombolytic therapy. Treatment is initiated when the SBP is greater
than 185 mm Hg or the DBP is greater than 110 mm Hg, and the goal is to
maintain the blood pressure below the treatment threshold [12,13].
226 rhoney & liu-deryke

Significance of hypertension in primary intracerebral hemorrhage

Patients with primary ICH admitted to the hospital were found to have
significantly higher blood pressure compared with patients with AIS [8,11,14].
Okumura and colleagues [8] demonstrated a U-shaped relation between the ad-
mission DBP and mortality in patients with primary ICH, whereas the SBP
seemed to have a J-shaped relation. A SBP greater than 190 mm Hg was asso-
ciated with a twofold risk of death, and the risk increased to fourfold when the
SBP was greater than 230 mm Hg. This relationship between elevated blood
pressure on hospital admission and poor clinical outcomes was confirmed by
several other studies [15–17]. There also seems to be a correlation between high
blood pressure and hematoma expansion, which is an independent factor for
further neurologic deterioration and poor clinical outcome. The causative re-
lationship between high blood pressure and hematoma expansion after sponta-
neous ICH remains debatable. Ohwaki and coworkers [18] examined the relation
between blood pressure and hematoma expansion in 76 patients with ICH.
Approximately 20% of patients experienced hematoma enlargement in which an
elevated SBP (160 mm Hg) was an independent factor for enlargement
(odds ratio [OR] = 1.041, 95% confidence interval [CI], 1.01–1.074). Conversely,
Kazui and colleagues [16] found that high SBP was a risk factor for hema-
toma expansion only in poorly controlled diabetes. Fujii and coworkers [19]
identified five independent risk factors for hematoma expansion; however, in-
creased blood pressure was not found to be a significant predictor. Whether
elevated blood pressure is the cause of hematoma expansion or vice versa is yet to
be delineated.
Because of the discovery of the penumbra in AIS, concern remains
regarding the potential adverse effects of blood pressure lowering during the
acute phase of ICH. In theory, possible ischemic events in the brain tissue
surrounding the hematoma may be associated with a rapid decrease in blood
pressure. Therefore, leaving the blood pressure alone after ICH may prevent
hypoperfusion and a subsequent ischemic event. The evidence for the penumbra
area in ICH is weak, however. In an experimental ICH model, Qureshi and
colleagues [20] examined the effect of MAP reduction on the regional cerebral
blood flow (rCBF) and whether ischemia existed around the periclot region.
Labetalol was administered 90 minutes after the introduction of ICH in dogs to
keep MAP greater than 65 mm Hg. Compared with control animals (surgery
only), no difference in rCBF was detected in any zone around the injury. More
importantly, an increase in ICP and MAP was observed after the induction of
ICH. A significant reduction in MAP was noted after administering labetalol;
however, no significant change in ICP and CPP was noted. A decrease in CVR
was observed, indicating that autoregulation was intact when the blood pressure
was lowered in a controlled fashion, and there was no evidence of periclot
ischemia in the acute phase of ICH. Similar findings were reported in clinical
studies (Table 1) [21–26]. In these studies, a reduction in the global CBF was
observed; however, it is suggested that the hypoperfusion was indicative of a
 cerebral circulation vasoactive therapy 227

Table 1
Autoregulation and ischemic penumbra in primary intracerebral hemorrhage
Study Design Significant findings
Kuwata et al 68 ICH patients No dysautoregulation was observed
[21] (1995) Antihypertensive agent: Acute phase: no effect on MAP with BP
trimethaphan or diltiazem reduction b20%
Carhuapoma et al 9 ICH patients Vasogenic edema was observed around
[22] (2000) the hematoma
DW MRI and proton No evidence of ischemia adjacent to
MR spectroscopic imaging the hematoma
Time to imaging: mean 3.4 days
Kidwell et al 12 ICH patients 6 patients underwent PWI: no focal ischemia
[23] (2001) around the hematoma
DWI and PWI 5 of 6 patients had ipsilateral hypoperfusion
Time to imaging: b6 hours
Zazulia AR et al 19 ICH patients Global decrease in CBF, CMRO2, and OEF
[24] (2001) in periclot region compared with contralateral
region
PET: 5–22 hours after onset No ischemia during the hyperacute stage
Powers et al 14 ICH patients No significant change in global CBF and
[25] (2001) rCBF after BP reduction
PET: 6–22 hours No correlation between reduction in MAP
and global CBF or rCBF
Antihypertensive agent: Autoregulation remained intact when MAP
nicardipine or labetalol lowered by 10%–22%
Lower MAP by 15%
Schellinger PD 32 ICH patients Perihematoma hypoperfusion indicating a
et al [26] (2003) reduced metabolic demand
DWI and PWI No signs of salvageable penumbra
Time to imaging: b6 hours
Abbreviations: BP blood pressure; CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of
oxygen consumption; DWI, diffusion-weighted imaging; DW MRI, diffusion-weighted magnetic
resonance imaging; ICH, intracerebral hemorrhage; MAP, mean arterial pressure; OEF, oxygen
extraction fraction; PET, positron emission tomography; PWI, perfusion-weighted imaging; rCBF,
regional cerebral blood flow.

reduction in cerebral metabolism during the hyperacute stage of ICH rather than
an ischemic event.
Because of the lack of convincing evidence of a penumbra area in acute
primary ICH and the potential relation to hematoma growth in the presence of
elevated blood pressure, blood pressure reduction during the acute phase of
primary ICH is likely to be safe. Moreover, autoregulation seems to be preserved
with controlled blood pressure lowering [21,25]. Powers and coworkers [25]
investigated the effect of blood pressure lowering on autoregulation of CBF in
patients with small to medium ICH (1–45 mL). They found that autoregulation of
CBF was not adversely effected when the lower MAP limit was 110 mm Hg or a
20% or less reduction from the baseline. Nevertheless, larger trials are needed to
(1) identify whether a penumbra area is present in patients with a large hematoma
volume (N 45 mL), (2) identify the safest lower limit for lowering blood pressure,
228 rhoney & liu-deryke

and (3) identify how fast the blood pressure should be lowered. Currently, a
National Institutes of Health (NIH)–funded study (NCT00226096) expecting
to enroll 4000 patients is underway to establish the effect of intensive blood
pressure lowering to different thresholds in acute ICH on morbidity and mor-
tality [27].

Pharmacotherapy

Thus far, evidence indicates that acute blood pressure management may be
beneficial in stroke to prevent neurologic deterioration; however, this needs to be
done in a controlled fashion, and moderation of blood pressure lowering is
important for preserving cerebral perfusion. Therefore, an ideal vasoactive agent
should have minimum cerebral effects (ie, CBF, ICP), a predictable dose response
(avoidance of precipitous drops in blood pressure that can lead to hypoperfusion
and end-organ damage), and rapid onset and offset of action. In addition, because
many patients have comorbidities, consideration should be given to the risk of
drug interactions and likelihood of exacerbating comorbid conditions. To help
clinicians make a rational choice as to whether blood pressure is deemed as
needing treatment, we now review the systemic and cerebral effects of commonly
used intravenous antihypertensive agents and their therapeutic application in
patients with stroke. Table 2 summarizes the physiologic and cerebrovascular
effects of selected intravenous antihypertensive agents.

Sodium nitroprusside

Cardiovascular effect
Nitroprusside is the most widely used parenteral agent for the management
of hypertensive crisis, attributed to its fast onset and short duration of action. It
is normally given as an intravenous infusion with immediate onset of action
and effects lasting 2 to 3 minutes after termination in relatively healthy individ-
uals [28]. Nitroprusside is a potent venous and arterial vasodilator, which results

Table 2
Systemic and cerebral physiologic effects of antihypertensive agents
Heart Cardiac Mean arterial Intracerebral Cerebral perfusion Cerebral
rate output pressure pressure pressure blood flow
Nitroprusside z zA A z A? zAX
Nitroglycerin z A A z A? A?
Esmolol A z A ? A? A?
Labetalol A z A X? A? X?
Nicardipine X z A X AX zX
Enalaprilat X zX A ? A? zX
Hydralazine z zA A z A zX
Fenoldopam zX z A z? A? A?
Abbreviations: z, increase; A, decrease; X , no change; ?, unknown.
 cerebral circulation vasoactive therapy 229

in a reduction in vascular resistance and, consequently, a reduction in preload and

afterload. These properties make nitroprusside useful in treating hypertensive
patients with underlying pulmonary edema or congestive heart failure. Mean-
while, studies suggest that nitroprusside can cause ‘‘coronary steal’’ through
redistribution of blood flow away from the heart, resulting in reduced coronary
perfusion pressure [29–31]. Other disadvantages of nitroprusside include tachy-
phylaxis and the need for a special delivery system because of its photosensitivity.
One of the major drawbacks of nitroprusside is the accumulation of toxic
metabolites, which has been associated with high doses, prolonged use, and end-
organ dysfunction. Nitroprusside contains 44% cyanide by weight, which is
released by smooth muscles in a dose-dependent manner. Cyanide toxicity results
from binding of cyanide to the heme molecule of mitochondrial cytochrome
oxidase, resulting in cellular hypoxia. In healthy individuals, toxic levels of cya-
nide can be expected in 500 minutes in an 80-kg adult receiving an infusion at a
rate of 2 mg/kg/min [32]. Monitoring for cyanide toxicity is often difficult, be-
cause the utility of cyanide concentrations is questionable; thus, monitoring is left
to clinical evaluation [33]. Tachyphylaxis is often thought to be an indication
of impending toxicity. In addition, a direct relation between lactic acidosis and
serum cyanide concentrations exists [34]. Cyanide is further metabolized by the
liver to thiocyanate and excreted through the kidney. Therefore, thiocyanate
toxicity is particularly problematic in patients with renal impairment, and it can
accumulate as soon as 3 days after an infusion is started. Cyanide and thiocyanate
toxicities can be difficult to diagnose, because symptoms (mostly of the central
nervous system [CNS]) are similar to those seen with CNS injury. Thus, the
possibility of cyanide or thiocyanate toxicity demands attention in all patients
receiving nitroprusside infusion, because toxicity can occur rapidly, be fatal, and
is difficult to identify in these patients.

Cerebrovascular effect
The theoretic concern of using nitroprusside in patients with brain injury is
that nitroprusside dilates cerebral vessels, unselectively resulting in an increase in
CBF and, consequently, ICP. Case reports and studies [35–37] have demonstrated
a direct correlation between increased ICP and nitroprusside infusion. Cottrell
and colleagues [35] demonstrated a linear relation between ICP and the degree
of blood pressure reduction in 10 patients with intracranial mass lesions. The
potential mechanism of increased ICP in these patients is that the intracranial
volume was disturbed because of the mass effect (ie, tumor, hematoma) and that
ICP increases as a result of administering an agent that can increase cerebral
blood volume. Concurrently, a significant decrease in CPP was observed during
nitroprusside infusion.
Nitroprusside and its effect on CBF are less clear because of mixed results
published in the literature. Data supporting that nitroprusside does not adversely
affect CBF were reported in several studies [38–41]. In one report [38], nine
patients received nitroprusside infusion under general anesthesia. CBF, cerebral
metabolic rate of oxygen consumption (CMRO2), CVR, and CPP were collected
230 rhoney & liu-deryke

before, during, and after the infusion. A reduction in CVR and CPP was ob-
served, along with a reduction in blood pressure. Changes in CBF and CMRO2
were insignificant throughout the study, however. In two patients who ex-
perienced a significant increase in CBF during the infusion, no major impact
on cerebral oxygen uptake was observed. There were also data indicating that
nitroprusside-induced hypotension resulted in an increase in CBF [35,42,43]; yet,
other studies reported that the use of nitroprusside was associated with a decrease
in CBF [44 –47].
Reasons for such variability in the cerebral response to nitroprusside are not
easily determined; however, many of these studies were conducted in the
operating suite. Differences in anesthetic technique (anesthetic agents are known
to affect CBF, CMRO2, ICP, CVR, and CPP), baseline comorbidities among
patients, type of neurologic injury, and the integrity of the autoregulatory sys-
tem may all contribute to such variation. Patients with impaired autoregulation
(eg, patients with stroke) are especially susceptible to the sudden change in
blood pressure. In these patients, a small reduction in blood pressure induced by
nitroprusside may result in significant changes in CBF and an increased ICP.
Hypo- or hyperperfusion may ensue and lead to further brain injury.

Therapeutic implications
In patients with preexisting impairment of cerebrovascular autoregulation, a
sudden variation in MAP induced by nitroprusside may exceed the capacity of
the cerebral circulation to autoregulate its flow. In addition, patients with an
intracranial mass (eg, hematoma) have an increased intracranial volume. This
increased volume causes an increase in ICP, and an abrupt drop in MAP can
decrease cerebral perfusion. Therefore, even though nitroprusside is still one of
the first-line agents recommended by stroke guidelines for acute hypertension
management, caution should be exercised; its use requires careful monitoring
of CBF, CPP, and ICP, especially in patients who may have altered intracranial
compliance or disturbances in autoregulation.

Nitroglycerin

Cardiovascular effect
Nitroglycerin is an organic nitrate and exhibits different pharmacologic effects
and toxicity profiles than nitroprusside. At lower doses, nitroglycerin is a potent
venodilator, causing a reduction in preload, and has little effect on arteriolar
resistance and systemic arterial pressure. At higher doses, nitroglycerin further
dilates venous smooth muscles as well as arterioles, which reduces arterial blood
pressure and activates sympathetic reflexes (compensatory mechanism). When
the compensatory mechanism fails under the prolonged venous pooling, serious
systemic hypotension and intravascular hypovolemia occur. Because nitroglyc-
erin dilates primarily capacitance and postcapillary resistance vessels, which ac-
count for approximately 80% of regional blood volume and 15% of pressure
drop, it is not an effective antihypertensive agent and its hypotensive effect is less
 cerebral circulation vasoactive therapy 231

predictable [30,48]. Nitroglycerin, however, is an effective antianginal agent

because of its ability to increase the collateral blood supply to the heart and
reduce oxygen consumption. The seventh report from the Joint National Com-
mittee recommends nitroglycerin for hypertensive patients with acute coronary
syndromes, such as myocardial infarction [26]. Nitroglycerin also causes arte-
riolar dilation in the face and neck irrespective of dose, resulting in flushing and
severe headache. Tolerance is likely to develop with continuous use, which re-
sults in attenuation of pharmacologic effects and generally is resolved with a
nitrate-free interval.

Cerebrovascular effect
Although the debate about using nitroprusside in patients with cerebrovascular
diseases continues, some have suggested using nitroglycerin as an alternative
based on limited data in cerebral vasospasm [49]. Headaches induced by
nitroglycerin suggest its dilatory effect on cerebral vessels, which introduces
similar concerns as with nitroprusside. Nitroglycerin is a more potent venodilator
than nitroprusside and has a greater effect on capacitance and resistance vessels;
therefore, it is more likely to increase CBF and cerebral volume. The net effect of
changes in cerebrovasculature is an elevation in ICP, which is more prominent in
patients with altered intracranial compliance. Studies examining the cerebral
effects of nitroglycerin are scarce. An increase in ICP after the initiation of
nitroglycerin has been described in a few experimental and human reports, par-
ticularly in patients with compromised autoregulation [50]. Gagnon and co-
workers [51] reported their experience with nitroglycerin in a 67-year-old man
with a brain tumor. Nitroglycerin was administered twice to this patient, whose
ICP had increased from 18 to 40 mm Hg and from 20 to 48 mm Hg, respectively.
Both incidences occurred within 2.5 minutes of nitroglycerin infusion. Similarly,
Ohar and colleagues [52] observed nitroglycerin-induced intracranial hyper-
tension in a 59-year-old woman with systemic hypertension and pulmonary hy-
pertension. This patient exhibited clinical symptoms of increased ICP, including
headache, vomiting, and progressive impaired consciousness. A lumbar puncture
was performed with an opening pressure of 210 mm H2O. This patient regained
consciousness, and her neurologic deficits were subsequently resolved after the
cession of nitroglycerin infusion.

Therapeutic implications
In neurologic patients with normal intracranial pathologic findings, short-term
use of nitroglycerin may be tolerated with transient increases in ICP. In patients
with suspected or documented elevated ICP (cerebral tumors or hematoma),
perfusion in the brain is particularly susceptible to any changes in blood pressure;
therefore, great caution should be exercised when using nitroglycerin in patients
with compromised intracranial compliance. Patients with concomitant myocardial
infarction may be candidates for nitroglycerin; however, the risk versus benefit
should be weighted before administering this agent. In addition, nitroglycerin
232 rhoney & liu-deryke

paste may not be an optimal antihypertensive agent in patients with stroke

because it is not easy to titrate and may have residual effects.

b-receptor antagonists

Cardiovascular effect
Esmolol and labetalol are the two most commonly used parenteral b-
adrenergic antagonists. Esmolol is a b1-selective antagonist with a rapid onset
of action and short half-life. It is metabolized by blood esterases; therefore, the
clearance of the drug is independent of liver and renal function. Esmolol is
primarily used for supraventricular tachycardia as well as for intraoperative or
postoperative hypertension. The major concern with this medication is that se-
vere bradycardia can develop before lowering of blood pressure is observed;
therefore, it is not routinely used for the treatment of a hypertensive crisis.
Unlike esmolol or other pure b-adrenergic antagonists, labetalol is a mixed a1-,
b1-, and b2-antagonist. Its beta-blockade activity is approximately seven times
that of alpha-blockade after intravenous administration. Because labetalol has
an effect on both adrenergic receptors, it possesses less of an effect on heart
rate and cardiac output compared with other beta-blockers. The onset of action of
labetalol is approximately 5 minutes. The duration of action is between 3 and
6 hours, which makes it difficult to titrate as a continuous infusion. Similar to
other b-antagonists, labetalol should be avoided in patients with first-degree heart
block, severe bradycardia, and asthma.

Cerebrovascular effect
The cerebrovascular effect of labetalol is primarily drawn from healthy
volunteers and chronic hypertensive patients. In 1979, Griffith and coworkers
[53] reported the effects of chronic use of four beta-blockers (labetalol,
metoprolol, oxprenolol, and sotalol) on blood pressure and CBF. A universal
reduction in blood pressure was observed as expected; however, no change in
CBF was observed before or after treatment. These authors concluded that beta-
blockers have little impact on cerebral circulation in the chronic setting but that
more research was warranted because their effects may vary during acute
administration. Another study [54] conducted in eight healthy normotensive
volunteers examined the effects of labetalol on blood pressure, global CBF and
rCBF, CMRO2, and cerebral autoregulation. Similar to previous findings, no
change in global CBF and rCBF or CMRO2 was detected. The autoregulatory
curve was successfully plotted in all participants, and there was no difference in
MAP before and after drug infusion. Results from this study indicated that
labetalol has little effect on cerebral circulation in the normal brain.
Despite a lack of data on cerebrovascular effects in patients with neuro-
logic injuries, labetalol has been widely used for blood pressure management in
these patients. Patel and colleagues [55] examined the efficacy (blood pressure
response) of labetalol in patients with hemorrhagic stroke. A moderate lowering
in blood pressure (3%–26%) was observed with doses ranging from 5 to 25 mg.
 cerebral circulation vasoactive therapy 233

In addition, no worsening of neurologic deficits occurred after administration of

the drug. Powers and coworkers [26] further examined the effect of systemic
blood pressure lowering on CBF using nicardipine or labetalol in patients with
ICH within 6 to 22 hours after onset. Fourteen patients were included in the study
(7 were given nicardipine and 7 were given labetalol); MAP and global and
periclot CBF were measured and compared with the patients’ own baseline. The
major conclusions were that a reduction in MAP, up to 20% from baseline,
seemed to be safe and that nicardipine and labetalol preserved autoregulation of
CBF in patients with ICH.

Therapeutic implication
On the basis of available data, labetalol seems to be a suitable antihypertensive
agent in patients with neurologic injuries because it did not demonstrate any
negative impact on CBF or autoregulation in healthy patients and patients with
ICH. Larger studies are needed to delineate the impact of labetalol on cerebral
circulation when autoregulation is impaired. A retrospective study [56] noted that
frequent boluses of labetalol were needed to achieve goal blood pressure,
requiring more nursing time and frequent monitoring. Further investigation
evaluating the effective labetalol dose and time to blood pressure response may
have an economic impact on clinical practice.

Calcium channel antagonists

Cardiovascular effect
Sublingual nifedipine was frequently given in the past for hypertensive
emergencies; however, reports of increased ischemic events and mortality cur-
tailed its use, primarily because of an unpredictable drop in blood pressure [29].
Nicardipine has gained popularity as a parenteral antihypertensive agent for
managing postoperative hypertension and hypertensive crisis in the past de-
cade, particularly in patients with brain injury. Nicardipine, a second-generation
dihydropyridine calcium channel blocker, is structurally similar to nifedipine.
With the addition of a tertiary amine, nicardipine is highly lipophilic and readily
crosses the blood-brain barrier (BBB). Because of its chemical structure, the salt
form of nicardipine is more water-soluble than nifedipine, which makes the in-
travenous preparation possible. Like other calcium channel blockers, nicardipine
inhibits the influx of calcium into cardiac and smooth muscle cells, causing
arteriolar vasodilation without a negative inotropic effect. The dose of nicardipine
is independent of body weight, and the onset of action is within 5 to 10 minutes.
Nicardipine has a relatively short duration of action (approximately 15 minutes)
because of its rapid redistribution [57]. These pharmacokinetic characteristics
allow for a titratable intravenous infusion.
Intravenous nicardipine has been shown to be as effective as nitroprusside in
lowering blood pressure. A multicenter prospective study described a more rapid
response to the goal blood pressure and less dosage adjustments with nicardipine
compared with nitroprusside [58]. The incidence of hypotension was slightly
234 rhoney & liu-deryke

higher with nitroprusside but not statistically significant. The efficacy of nicardi-
pine compared with nitroprusside was also evaluated after surgery in patients
who underwent carotid endarterectomy [59]. A more predictable therapeutic re-
sponse (less variation in blood pressure) was observed with nicardipine than with
nitroprusside. Fewer patients who received nicardipine compared with those who
received nitroprusside required dosage adjustments. Results from these studies
suggest that nicardipine is at least as effective as nitroprusside in lowering blood
pressure and provides a more predictable response with less dosage adjustments.

Cerebrovascular effect
Nicardipine has generated great interest in its therapeutic role in treating
cerebrovascular diseases, primarily because of its calcium blockade property and
high cerebrovascular selectivity [60–62]. Because nicardipine is a vasodilator,
one may question whether nicardipine increases CBF and adversely affects ICP
like nitroprusside or nitroglycerin. Experimental and human data have indicated
that nicardipine can increase CBF; however, it has little effect on ICP while
lowering blood pressure. Unlike nitrovasodilators, nicardipine does not dilate all
cerebral vessels, which may cause profound hypotension and cerebral ischemia.
Gaab and coworkers [62] demonstrated that nicardipine dilates small-resistance
arterioles with no significant changes in intracranial volume and ICP. Although
MAP and CPP decreased significantly, CPP was within the critical level of auto-
regulation. Similarly, Nishiyama and colleagues [63] reported that nicardipine
infusion in patients with ICH was safe and effective despite a slight decrease
in CPP. The reported CPP was 99 F 17 mm Hg at baseline, 75 F 14 mm Hg
at 24 hours of infusion, and 73 F 15 mm Hg at 72 hours of infusion. No nega-
tive clinical consequences were observed with the nicardipine infusion in this
study. As described previously, Powers and coworkers [25] also reported that
nicardipine effectively reduced blood pressure up to 20% from baseline in pa-
tients with ICH without compromising autoregulation. In our own experience,
nicardipine produced a moderate reduction in blood pressure and required less
dosage adjustments and less additional antihypertensive agents compared with
labetalol in patients with stroke [64].
In addition to the safety data in cerebral hemodynamics, nicardipine has been
investigated for its potential neuroprotective effect. Because calcium plays an
important role in propagating free oxygen radicals and subsequent neuronal
injury after stroke, it is intuitive to speculate that a calcium antagonist may
potentially attenuate further insult and improve neurologic recovery [65,66].
Earlier studies in spontaneous hypertensive rats suggested that nicardipine
reduced neuronal cell death; however, current data supporting the neuroprotective
effect of nicardipine are scarce. Future research is needed to determine the
neuroprotective role of nicardipine.

Therapeutic implications
Nicardipine is an effective antihypertensive agent and has been used for
hypertensive emergency. In addition to its effectiveness, studies have shown that
 cerebral circulation vasoactive therapy 235

nicardipine is easy to titrate and produces less variability while lowering blood
pressure. Furthermore, it may have a pivotal role in treating hypertensive-related
neurologic disorders because of its favorable cerebral hemodynamic effects.

Renin-angiotensin system blockade

Cardiovascular effect
The renin-angiotensin cascade has been known to contribute to the hyper-
tensive state. Angiotensin-converting enzyme inhibitors (ACEIs) have been used
in the treatment of chronic hypertension and congestive heart failure for many
years. These agents are thought to be effective for hypertension via several
mechanisms: (1) increasing concentrations of the local vasodilator bradykinin,
(2) decreasing concentrations of angiotensin II, and (3) inhibiting the local
vascular effects of angiotensin II. In patients with hypertension, ACEIs decrease
total peripheral resistance but cause little change in heart rate, cardiac output,
or pulmonary occlusion pressures [67]. In patients with congestive heart fail-
ure, however, cardiac output may increase in response to the afterload reduc-
tion [68].

Cerebrovascular effect
The effect of captopril on CBF has been extensively studied in rats and human
beings. In general, studies that have evaluated renin-angiotensin system (RAS)
blockade using ACEIs have shown increases in CBF with a shift in the
autoregulatory curve [69–75]. This is in contrast to the direct vasodilators, which
increase CBF and inhibit cerebral autoregulation.
In normotensive or spontaneously hypertensive rats, intravenously adminis-
tered captopril shifts the upper (by 50–60 mm Hg) and lower (by 20–30 mm Hg)
limits of the autoregulatory curve, and subsequently shortens the plateau of the
curve by 20 to 40 mm Hg [72]. The mechanism by which ACEIs affect CBF is
via inhibition of angiotensin II–mediated vascular tone in the large cerebral ar-
teries while the small-resistance vessels constrict [76,77]. Therefore, in response
to blood pressure decreases, these vessels dilate so that there is less capacity
for vasoconstriction when the blood pressure is elevated. In patients with heart
failure, captopril resulted in a reduction of blood pressure with no change in CBF
[71] or an increase in CBF [69], suggesting an acute shift of the autoregulatory
curve toward lower pressure. In patients with recent ischemic cerebral infarcts
(2–7 days), the use of ACEIs reduced blood pressure without adversely affecting
middle CBF velocity or global CBF in patients with and without carotid artery
disease [70,74,75,78,79].
The effects of ACEIs on ICP have not been extensively studied. In patients
with normal pressure hydrocephalus, captopril reduced MAP by 16 mm Hg
without any effects on CBF or ICP [80]. There are currently no studies published
evaluating patients with altered intracranial compliance and subsequent effects of
236 rhoney & liu-deryke

ACEIs on ICP, although with their effects on CBF, there may be a potential for
increases in ICP in these patients.
The use of angiotensin receptor blocking agents (ARBs) has recently been
investigated. The Acute Candesartan Cilexetil Therapy in Stroke Survivors Trial
(ACCESS) compared the use of candesartan (4–16 mg) with acute (b 72 hours)
versus delayed (N 7 days) initiation of therapy in 342 hypertensive (N180/105 mm
Hg) patients with AIS [81]. The study was halted prematurely because of a sig-
nificant reduction in the secondary end point (combined death, recurrent stroke,
cardiac events, and dependency at 2 months; OR = 0.475, 95% CI, 0.252–0.895).
The primary end point (death and disability at 3 months) was unchanged, how-
ever. There were no adverse cerebral effects reported with the acute use of this
agent. Nazir and coworkers [82] observed that losartan could safely be introduced
within 2 to 7 days of mild stroke in patients with hypertension and significant
carotid disease without affecting global CBF or rCBF.
The use of agents affecting the RAS may extend beyond their blood pressure
lowering properties. This system may adversely influence fibrinolytic balance,
vascular endothelial function, and vascular inflammation, which are all key
components of atherosclerotic progression and subsequent adverse vascular out-
comes. Studies have suggested that ACEIs and ARBs may have favorable effects
on various substances, including plasminogen activator inhibitor-1, endothelin-1,
nitric oxide, vascular cell adhesion molecule-1, and C-reactive protein [83]. In
clinical trials of antihypertensive therapy, however, monotherapy with ACEIs has
failed to prevent primary stroke beyond their general effects on blood pressure
[84,85]. In contrast, studies like the Losartan Intervention for Endpoint Reduction
in Hypertension (LIFE) study have shown that the ARB losartan significantly
prevented primary stroke compared with atenolol [86]. Some investigators have
hypothesized that ARBs (which increase angiotensin II levels and stimulate the
angiotensin type-2 receptor) have superior cerebroprotective properties compared
with ACEIs [87]. In gerbils, at comparable blood pressure lowering effects, pre-
administration of an ARB had a lower incidence of mortality than preadminis-
tration of an ACEI. When the ACEI and the ARB were administered together,
however, no reduction in the incidence of mortality was observed [88]. Therefore,
ARBs may have superior mechanisms of action compared with ACEIs in that
they inhibit the angiotensin type-1 receptor–mediated proatherothrombotic ef-
fects and enhance the angiotensin type-2 receptor–mediated cerebroprotection by
increasing the generation of angiotensin II. Because ACEIs reduce circulating
angiotensin II concentrations and subsequent angiotensin type-2 receptor cerebro-
protection, their effects in blunting the proatherothrombotic effects mediated by
the angiotensin type-1 receptor may be mitigated.
Activation of vascular angiotensin type-2 receptor has been shown to induce
vasodilation by local synthesis of nitric oxide and prostacyclin. In the ischemic
brain, there is overexpression of angiotensin type-2 receptors [89]; thus, collateral
circulation may increase in ischemic areas. Chronic pretreatment and posttreat-
ment with angiotensin type-1 receptor blocking agents in the rat brain improved
neurologic outcome, infarct volume, and cerebral edema after cerebral ischemia
 cerebral circulation vasoactive therapy 237

[90–95]. The results of the ACCESS study suggest that the use of ARBs is safe
during the acute period, and a study is warranted to evaluate the potential
vascular protective mechanisms associated with these agents acutely.

Therapeutic implications
There are many different agents that are available orally. Enalaprilat is cur-
rently the only available intravenous ACEI available in the United States,
whereas an intravenous formulation of ARB is currently unavailable. The use of
ACEIs or ARBs for the treatment of acute hypertension after stroke may seem
appealing; however, the only intravenous agent available is associated with some
disadvantages that may limit the widespread use of this agent acutely. Enalaprilat
has an onset of action within 15 minutes; however, the duration of action is 12 to
24 hours. Furthermore, Hirshcl and coworkers [96] demonstrated that the degree
of blood pressure reduction associated with this agent is related to the pre-
treatment concentration of angiotensin II and plasma renin activity. Because of
the unpredictability of the response and long duration of action, the routine use of
this agent to lower blood pressure acutely after an acute cerebrovascular event
cannot be recommended. Future studies may show a neuroprotective effect of
these agents; thus, ACEIs or ARBs may become part of the treatment regimen
outside of their blood pressure lowering properties.

Other agents

Fenoldopam
Fenoldopam is a peripheral dopamine-1 receptor agonist, with its antihyper-
tensive effects attributable to a combination of direct vasodilation and renal-
arterial dilation with natriuresis [97]. It does not bind to the dopamine-2 receptors
or b-adrenergic receptors or possess a-adrenergic agonist effects; however, it is
an a2-antagonist [30]. Therapeutic doses of fenoldopam reduce SBP and DBP,
with an increase in heart rate proportional to this decrease. Renal vascular resis-
tance decreases, whereas renal blood flow and glomerular filtration rate increase.
These effects seem to be greater in the hypertensive population. Fenoldopam
is poorly soluble in lipids, does not cross the BBB, and has no CNS effects in
patients with an intact BBB [98].
Dopamine has a wide spectrum of effects that could ultimately affect CBF.
The effects of fenoldopam on cerebral circulation are poorly defined in patients
with acute stroke. In nine normotensive healthy volunteers (with autoregulation
presumed to be intact), fenoldopam-induced hypotension significantly decreased
global CBF [99]. Hennes and Jantzen [100] evaluated the effects of fenoldopam
on ICP under conditions of normal and increased intracranial elastance in pigs.
Fenoldopam did not increase ICP when ICP was normal; however, under con-
ditions of elevated ICP, fenoldopam resulted in increases in ICP, suggesting a
shift in the volume-pressure curve to the right. This study did not find that
fenoldopam affected cerebral autoregulation or carbon dioxide reactivity [100].
238 rhoney & liu-deryke

Reports on this experimental model would suggest that fenoldopam should be

used in caution in patients with altered intracranial compliance.
The onset of clinical effects is rapid (within 5 minutes), and effects disappear
within 30 minutes from termination of the infusion. Common adverse effects
include headache, flushing, tachycardia, dizziness, and a dose-related increase in
intraocular pressure. The clinical utility of this agent in patients with cerebro-
vascular disease is limited until further information is available to assess its
effects acutely in these patients.

Hydralazine
Hydralazine is a direct-acting smooth muscle relaxant that causes vasodilation
to a greater extent in arteries than in veins. It acts by interference with vascular
smooth muscle calcium transport and has also been shown to generate nitric
oxide [101]. In animals without intracranial pathologic changes, small increases
in ICP with no alteration or small increases in CBF have been reported [102]. In
patients with severe brain injury, administration of hydralazine resulted in in-
creases in ICP with defective or absent cerebral autoregulation [103,104]. CBF
remained stable or slightly increased in these patients despite the increases in ICP.
Hydralazine causes reflex stimulation of the sympathetic nervous system, with
increases in ICP in patients with head injury [105]. This effect can be blunted by
coadministration of b-receptor antagonists. The onset of action of hydralazine is
within 15 minutes, with a half-life of 3 hours; however, the half-time of its effect
on blood pressure is approximately 100 hours [106]. Because of its prolonged and
unpredictable antihypertensive effects in addition to the effects reported on the
cerebrovasculature, hydralazine should be avoided in patients with acute stroke.

Summary

Controversy surrounds the ideal management of blood pressure during the

acute phase of stroke. The primary goal in acute blood pressure management in
these patients is to avoid further insults to the brain and minimize neurologic
deficit. Evidence suggests that the initial elevation of blood pressure may be
a protective mechanism to ensure adequate blood perfusion to the brain. Par-
ticularly in ischemic stroke, elevated blood pressure may be essential to the
penumbra area, where blood flow is pressure dependent. More aggressive blood
pressure lowering can be applied in ICH compared with AIS, because evidence
suggests the absence of a periclot penumbra; however, precipitous drops in blood
pressure may still induce ischemia and should be avoided. Conversely, studies
also demonstrate that severe hypertension may exacerbate brain edema or induce
a hemorrhagic event. Although debate continues, many practitioners think that
it is necessary to treat severe hypertension with a moderate lowering of blood
pressure [12,13,107].
When treatment is deemed necessary, blood pressure should be lowered
cautiously during the first 24 hours so as to avoid further ischemia to the brain
 cerebral circulation vasoactive therapy 239

tissue. Therefore, a short-acting, titratable, and predictable agent should be used.

Nitroprusside has been widely used in managing hypertensive crisis and is
recommended in current guidelines [12,13,107]; however, its potential effect on
increasing ICP cannot be ignored. In addition, cyanide or thiocyanate toxicity is a
major concern and difficult to diagnose, especially in patients with impaired
mental status after stroke. Based on limited clinical evidence, labetalol and
nicardipine seem to produce moderate and predictable reductions in blood
pressure with minimal effect on the cerebrovasculature. Currently, there are no
comparative trials of these two agents to demonstrate equivalency or superiority
in the acute setting. Future comparative studies should evaluate clinical end
points, such as time to goal blood pressure, degree of blood pressure reduction,
and safety. There are many unanswered questions related to blood pressure
management after AIS or ICH. Large clinical trials are necessary to delineate the
threshold for initiation of therapy, the appropriate degree of blood pressure
reduction and the resultant impact on clinical outcomes, and the timing of acute
blood pressure management in these patients.

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